Vascular smooth muscle (VSM) cyclic guanosine 3',5'-moriophosphate (cGMP) serves as a critical[unreadable] regulator of many cellular functions that contribute to vessel growth after injury. Nitric oxide (NO) and[unreadable] carbon monoxide (CO) operate as soluble guanylate cyclase (sGC)-activating ligands for cGMP synthesis;[unreadable] however, limitations of NO and CO signaling warrant study into alternate, pathophysiologically relevant[unreadable] routes for cGMP control. Provocative new findings challenge the traditional notion that cGMP exerts[unreadable] vascular protection through cGMP-dependent protein kinase type (cGKI) and suggest that cGMP may[unreadable] operate via cAMP/cAK to promote vascular protection. Current studies in our laboratory focus on novel NOindependent[unreadable] approaches for cGMP control as significant basic science tools and as potential cardiovascular[unreadable] therapeutics. Preliminary data support a role for vascular growth control by NO-independent cGMP and[unreadable] suggest mechanistic involvement of matrix metalloproteinase (MMP)-2 and MMP-9. The long-term objective[unreadable] of this research project is to investigate strategies for cGMP control of VSM growth, and the central[unreadable] hypothesis of this proposal is that NO-independent cGMP protects against vascular growth and that this[unreadable] occurs through cAK signals. Two Specific Aims will be used to test this hypothesis:[unreadable] Aim 1 will analyze the roles of NO-independent cGMP and cGMP-directed cGKI/cAK signaling in[unreadable] attenuating vascular remodeling in the rat balloon injury and mouse wire denudation injury models.[unreadable] Aim 2 will examine matrix-based mechanisms including cell migration and MMP balance that underlie[unreadable] cGMP-mediated growth control in rat and mouse primary VSM cells.[unreadable] Pharmacology, RNA interference, and viral gene delivery approaches will be used, and conditional VSMspecific[unreadable] cGKI-deficient models will allow direct comparison of cGKI versus cAK mechanisms. Results are[unreadable] anticipated to provide insight into and further evidence for NO-independent cGMP control of the injury[unreadable] growth response in VSM and shed light upon cGMP-directed MMPs in mediating these events.[unreadable] Injuries and diseases of the heart and blood vessels are wide-ranging and very serious public health[unreadable] concerns, and statistics show they are still the major cause of death in American populations. We believe[unreadable] that results from these studies will shed light on some novel and promising strategies that could be used to[unreadable] minimize the severity of blood vessel injury and disease and may offer beneficial prospects for further study[unreadable] in basic science research and human-based clinical studies.[unreadable]